Severe microcephalyGene: RBBP8
Comment on list classification: Updated rating from Red to Green: 3 unrelated cases of variants of Seckel syndrome (MIM:606744) or Jawad syndrome (MIM:251255). Plus an additional 2015 case PMID:26333564 that may or may not represent a related family. Additional evidence comes from PMID:24440292 where NRXN1 may also be involved.
2 Mar 2017, 9:27 a.m.
PMID:24440292 (Agha et al., 2014) report a consanguineous Pakistani family with severe congenital micropcephaly in 2 affected brothers. The brothers carried the c.919A>G, p.Arg307Gly mutation. The brothers and their mother (mildly affected) also carried a heterozygous 607kb deletion encompassing exons 13-19 of NRXN1.
28 Feb 2017, 10:29 a.m.
PMID:26333564 (Mumtaz et al., 2015) report on a consanguineous Pakistani family with homozygous RBBP8 mutation c.1808_1809delTA (rs587776884, p.Ile603Lysfs*7) in at least 4 affected siblings (2 males, 2 females) manifesting microcephaly (amongst other symptoms). This is the same mutation as reported in the Pakistani family examined by Qvist et al., 2011 (PMID:21998596) so it is unclear if this represents a separate case like the authors suggest.
28 Feb 2017, 10:29 a.m.
In a 9 year old Saudi Arabian girl with Seckel syndrome-2, Shaheen et al. 2014 (PMID:24389050) identified homozygosity for a
c.298C-T transition (R100W) in RBBP8.
28 Feb 2017, 9:54 a.m.
Qvist et al., 2011 (PMID:21998596) examined 2 unrelated microcephalic families- an Iraqi family with Seckel syndrome-2 (MIM:606744) and a Pakistani family with Jawad syndrome (MIM:251255). They identified a homozygous splice site mutation in 4 affected sibs from consanguineous Iraqi family with Seckel syndrome-2; Unaffected parents were both heterozygous and the mutation was not found in 100 controls. The mutation acts as a dominant negative. In the consanguineous Pakistani family with Jawad syndrome, Qvist identified a 2bp homozygous deletion in RBBP8 causing frameshift and premature termination; the mutation was heterozygous in carriers and not found in controls.
28 Feb 2017, 9:53 a.m.
2nd March 2017: Panel review was assessed and panel was revised according to expert review and additional curation. This panel began with an expert gene list from Professor Andrew Jackson (University of Edinburgh) for primary microcephaly (MCPH) and microcephalic primordial dwarfism (MPD). Other disorders are included where microcephaly is a primary feature. Disorders where microcephaly is not the primary presenting feature are not included (e.g. congenital disorders of glycosylation, Proud syndrome, Norrie disease). The panel does not include disorders with a cortical malformation (e.g. lissencephaly) since the Malformations of cortical development' panel would be applied to these patients.
This gene has been classified as Green List (High Evidence).
Phenotypes for RBBP8 were set to MCPH; primary microcephaly; Seckel syndrome 2, 606744 (includes microcephaly); MICROCEPHALIC PRIMORDIAL DWARFISM 2; Jawad syndrome (microcephaly with mental retardation and digital anomalies), 251255; Jawad syndrome, 251255 (includes congenital microcephaly)
RBBP8 was added to Primary Microcephaly - Microcephalic Dwarfism Spectrumpanel. Source: Other Model of inheritance for gene RBBP8 was set to BIALLELIC, autosomal or pseudoautosomal
RBBP8 was created by rfoulger
RBBP8 was added to Primary Microcephaly - Microcephalic Dwarfism Spectrumpanel. Sources: Expert list